The most common genetic entity in childhood acute lymphoblastic leukemia (ALL) is associated with a[unreadable] t(12;21) chromosomal translocation that leads to expression of the fusion protein TEL-AMLl/runx1 from the[unreadable] TEL locus. Epidemic logical studies demonstrate that the TEL-AML1 fusion is present as a somatic mutation[unreadable] in newborns at a frequency at least 10-fold higher than the incidence of ALL. Hence, it is believed that[unreadable] additional events are required, including loss of function of the other TEL allele (as occurs in the vast[unreadable] majority of TEL-AML1 ALL). Current therapy of childhood ALL, though effective, is empirical and[unreadable] potentially toxic. Drug therapy targeted to genetic lesions in ALL offers the possibility of reducing morbidity[unreadable] while retaining efficacy. In order to approach this, a valid preclinical model of ALL is required. The goal[unreadable] here is to generate a model of TEL-AML1 leukemia in the mouse that accurately reflects the pathogenetics in[unreadable] man. We have generated conditional mutant mouse strains that permit activation of the TEL-AML1 fusion[unreadable] gene from the endogenous TEL locus (hence, at an appropriate expression level) and inactivation of TEL[unreadable] function either during embryogenesis or later in life. Activation of TEL-AML1 expression leads to a block in[unreadable] lymphopoiesis, expansion of a c-kit+ progenitor population, but no progression to frank leukemia. Thus,[unreadable] expression of the fusion protein from the endogenous TEL locus interferes with normal lymphoid[unreadable] development and appears to generate a "preleukemic" state. Our current aims (1) characterize further the[unreadable] preleukemic phenotype and the properties of the expanded c-kit+ population in TEL-AML1 expressing mice;[unreadable] (2) determine the phenotype of mice in which TEL-AML1 expression is activated later in hematopoiesis,[unreadable] specifically within the B-lymphoid lineage by intercrosses of flox-stopped TEL-AML1 mice with CD2-cre[unreadable] mice; (3) perform retroviral insertional mutagenesis in mice from (1) and (2) in order to convert preleukemia[unreadable] to leukemia and identify in vivo complementing genes; and (4) functionally test candidate tyrosine kinases[unreadable] identified in the Project 1 to complement mice in (I) and (2) and generate frank leukemia following retroviral[unreadable] gene transfer. These studies should lead to generation of mice that accurately model childhood ALL.